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Additive Beneficial Effects of Losartan Combined With
Simvastatin in the Treatment of Hypercholesterolemic,
Hypertensive Patients
Kwang Kon Koh, MD; Michael J. Quon, MD, PhD; Seung Hwan Han, MD; Wook-Jin Chung, MD; Jeong Yeal Ahn, MD; Yiel-Hea Seo, MD; Moon Ho Kang, MD; Tae Hoon Ahn, MD; Background—Biological mechanisms underlying statin and angiotensin II type 1 receptor blocker therapies differ.
Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination inhypercholesterolemic, hypertensive patients.
Methods and Results—This was a randomized, double-blind, placebo-controlled crossover trial with 3 treatment arms
(each 2 months) and 2 washout periods (each 2 months). Forty-seven hypertensive, hypercholesterolemic patients weregiven simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 mg, or losartan 100 mg and placebo dailyduring each 2-month treatment period. Losartan alone or combined therapy significantly reduced blood pressurecompared with simvastatin alone. Compared with losartan alone, simvastatin alone or combined therapy significantlychanged lipoproteins. All 3 treatment arms significantly improved flow-mediated dilator response to hyperemia anddecreased plasma malondialdehyde and monocyte chemoattractant protein-1 levels relative to baseline measurements.
However, these parameters were changed to a greater extent with combined therapy compared with simvastatin orlosartan alone (both PϽ0.001 and Pϭ0.030 for monocyte chemoattractant protein-1 by ANOVA). Combined therapyor losartan alone significantly increased plasma adiponectin levels and insulin sensitivity (determined by QUICKI)relative to baseline measurements. These changes were significantly greater than in the group treated with simvastatinalone (PϽ0.001 for adiponectin, Pϭ0.029 for QUICKI by ANOVA).
Conclusions—Simvastatin combined with losartan improves endothelial function and reduces inflammatory markers to a
greater extent than monotherapy with either drug in hypercholesterolemic, hypertensive patients. (Circulation. 2004;
110:3687-3692.)
Key Words: angiotensin Ⅲ endothelium Ⅲ hypercholesterolemia Ⅲ hypertension Ⅲ insulin
Hypercholesterolemia and hypertension are major public onset of new diabetes.1,4 The mechanisms of this benefit may health problems that are frequently treated with statins relate to the ability of these therapies to reduce insulin and angiotensin II type 1 (AT1) receptor blockers, respec- resistance.5 Moreover, it is possible that simvastatin com- tively. Although the mechanisms of action for these 2 classes bined with losartan therapy may have additional vascular of drugs differ, both classes have beneficial effects on the benefits that are greater than those observed for either drug vasculature. Indeed, large-scale clinical studies have demon- strated that simvastatin, an HMG-CoA reductase inhibitor, Statins reduce LDL cholesterol. In addition, they improve and losartan, an AT1 receptor blocker, prevent and retard the endothelial function via stimulation of nitric oxide (NO) progression of coronary heart disease.1,2 Hypertension and synthase activity and mediate antioxidant effects that result in coronary heart disease are frequently associated with insulin enhanced NO bioactivity.6,7 AT1 receptor blockers also resistance and disorders of metabolic homeostasis such as improve endothelial function.8,9 This may be due in part to obesity and type II diabetes. The endothelial dysfunction diminished intracellular production of superoxide anions via associated with cardiovascular diseases may contribute to reduced activity of angiotensin II– dependent oxidases.10 insulin resistance and the pathophysiology of diabetes and its Inhibition of the production of superoxide anions may limit vascular complications.3 In fact, large-scale clinical studies oxidation of LDL and contribute to increased NO bioactivity have demonstrated that simvastatin and losartan reduce the by limiting oxidative degradation of NO.7 Thus, AT1 receptor Received June 5, 2004; revision received July 27, 2004; accepted July 27, 2004.
From Cardiology (K.K.K., S.H.H., W.-J.C., T.H.A., I.S.C., E.K.S.), Laboratory Medicine (J.Y.A., Y.-H.S.), and Endocrinology (M.H.K.), Gachon Medical School, Incheon, Korea, and Diabetes Unit, Laboratory of Clinical Investigation, NCCAM, NIH (M.J.Q.), Bethesda, Md.
Correspondence to Kwang Kon Koh, MD, PhD, FACC, FAHA, Professor of Medicine, Director, Vascular Medicine and Atherosclerosis Unit, Cardiology, Gil Heart Center, Gachon Medical School, 1198 Kuwol-dong, Namdong-gu, Incheon, Korea. E-mail kwangk@ghil.com 2004 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000143085.86697.13
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Baseline Characteristics of the Study Population
frequently) during the study. Calcium channel or ␤-adrenergicblockers were withheld for Ն48 hours before the study to avoid the effects of these drugs. The Gil Hospital Institute Review Board approved the study, and all participants gave written, informedconsent.
Laboratory Assays
Blood samples for laboratory assays were obtained at approximately8 AM after patients fasted overnight before and at the end of each 2-month treatment period. These samples were immediately coded so that investigators performing laboratory assays were blinded to subject identity or study sequence. Assays for lipids, glucose, andplasma malondialdehyde (MDA), monocyte chemoattractant protein BMI indicates body mass index. Values are expressed as meanϮSEM when (MCP)-1, and adiponectin were performed in duplicate by ELISA (BIOXYTECH LPO-586, OxisResearch, and R&D Systems, Inc)and assays for high-sensitivity C-reactive protein (hsCRP) levels by latex agglutination [CRP-Latex(II), Denka-Seiken] as previously described.7,8,18 Assays for plasma insulin levels were performed in The endothelial dysfunction associated with diabetes, obe- duplicate by immunoradiometric assay (INSULIN-RIABEAD II,Abbott Japan). The interassay and intra-assay coefficients of varia- sity, metabolic syndrome, and other insulin-resistant states is tion were Ͻ6%. Quantitative Insulin-Sensitivity Check Index characterized by impaired NO release from endothelium.12 (QUICKI), a surrogate index of insulin sensitivity, was calculated as Thus, improvement in endothelial function is predicted to follows (insulin is expressed in ␮U/mL and glucose in mg/dL): enhance insulin sensitivity, and this may be a mechanism by QUICKIϭ1/[log(insulin)ϩlog(glucose)].19 which simvastatin and losartan decrease the incidence of Vascular Studies
new-onset diabetes. Adiponectin is one of a number of Imaging studies of the right brachial artery were performed with an proteins secreted by adipose cells that may couple regulation ATL HDI 3000 ultrasound machine (Bothell) equipped with a of insulin sensitivity with energy metabolism and serve to 10-MHz linear-array transducer based on a previously published link obesity with insulin resistance.13 In humans, plasma technique.7,8,18,20 Measurements were performed by 2 independent levels of adiponectin are negatively correlated with adiposity, investigators (S.H.H. and W.-J.C.) blinded to the subject’s identity and decreased plasma adiponectin levels are observed in and medication status. Measurements of maximum diameter andpercent flow-mediated dilation were made in 10 studies selected at patients with diabetes and those with coronary artery dis- random. The interobserver and intraobserver variabilities for re- ease.14,15 Thus, decreased levels of adiponectin may play a peated measurement of maximum diameter were 0.01Ϯ0.06 and key role in the development of insulin resistance. In addition, 0.008Ϯ0.05 mm, respectively. The interobserver and intraobserver adiponectin also possesses antiatherogenic properties.16,17 variabilities for repeated measurement of percent flow-mediated Because the impact of simvastatin and losartan therapies dilation were 0.12Ϯ1.31% and 0.10Ϯ1.29%, respectively.
on NO bioactivity and its subsequent effects on oxidant Statistical Analysis
stress, inflammation, endothelial function, and insulin resis- Data are expressed as meanϮ SEM or median (25% to 75% range).
tance may differ, we hypothesized that combined therapy After testing data for normality, we used Student’s paired t or may have additive beneficial effects that are greater than Wilcoxon signed-rank test to compare values before and after each those observed with either simvastatin or losartan therapy treatment and the relative changes in values in response to treatment, alone in hypercholesterolemic, hypertensive patients.
as reported in Tables 2 and 3. The effects of the 3 therapies onvascular function, markers of oxidant stress and inflammation, andinsulin sensitivity relative to baseline values were analyzed by 1-way repeated-measures ANOVA or Friedman’s repeated ANOVA on Study Population and Design
ranks. After demonstration of significant differences among thera-pies by ANOVA, post hoc comparisons between treatment pairs Fifty hypercholesterolemic, hypertensive patients (LDL cholesterol were made by use of the Student-Newman-Keuls multiple compar- levels Ն100 mg/dL) participated in this study. We defined hyper- ison procedures. Pearson’s correlation coefficient analysis was used tension as systolic and diastolic blood pressure Ն140 or to assess associations between measured parameters. We calculated 90 mm Hg, respectively. We excluded patients with severe hyper- that 30 subjects would provide 80% power for detecting a difference tension, unstable angina, or acute myocardial infarction. To mini- of absolute increase, Ն2.1% flow-mediated dilation of the brachial mize acute side effects to losartan, study medication was titrated artery between baseline and simvastatin, with ␣ϭ0.05 based on our from 50 to 100 mg upward over a 2-week period if no hypotension previous studies.7,20 The comparison of endothelium-dependent di- (systolic blood pressure Ͻ100 mm Hg) was noted. At the end of this lation among the 3 treatment schemes was prospectively designated time, participants were receiving either placebo or losartan 100 mg/d.
as the primary end point of the study. All other comparisons were Of 50 patients, 47 tolerated losartan 100 mg with regard to considered secondary. A value of PϽ0.05 was considered statisti- maintaining systolic blood pressure Ͼ100 mm Hg for 3 hours after drug administration and experienced no adverse effects from ther-apy. One patient was hypotensive, and the other 2 patients sufferedfrom dry cough. Thus, a total of 47 patients’ data were analyzed. The clinical characteristics of these patients are summarized in Table 1.
When baseline values before each treatment period were Patients were randomly assigned to one of the 3 treatments: compared among the 3 treatment arms, no significant differ- simvastatin 20 mg and placebo, simvastatin 20 mg and losartan 100 ences were noted in any of the parameters measured (Tables mg, or losartan 100 mg and placebo daily during 2 months. This was 2 and 3). To rule out the possibility of a carryover effect from a randomized, double-blind, placebo-controlled study with 3 treat-ment arms (each 2 months) and crossover with 2 washout periods one treatment period to the next, we compared baseline (each 2 months). The patients were seen at 14-day intervals (or more values before the first treatment period to those before the Simvastatin Combined With Losartan
3689
Effects of Simvastatin, Combined Therapy, and Losartan on Lipid Levels and Endothelial Function in Hypercholesterolemic,
Hypertensive Patients
S indicates simvastatin; C, combined therapy; L, losartan; BP, blood pressure; Apo, apolipoprotein; and NTG, nitroglycerin. Data are expressed as meanϮSEM or median (25th to 75th percentiles). There were no significant differences among each baseline value.
*PϽ0.05, †PϽ0.01, ‡PϽ0.001 vs each baseline value.
second and third treatment periods. There were no significant hyperemia relative to baseline measurements by 38Ϯ4%, differences in any of the measured parameters in this analysis.
68Ϯ4%, and 31Ϯ3%, respectively (all PϽ0.001); however,combined therapy significantly improved this response more Effects of Therapies on Blood Pressure and Lipids
than simvastatin or losartan alone (PϽ0.001 by ANOVA; Losartan alone or combined therapy significantly reduced sys- Figure 1 and Table 2). The brachial artery dilator response to tolic and diastolic blood pressures after 2 months of administra- nitroglycerin was similar for all therapies and was not tion compared with baseline. These reductions were signifi- significantly changed from baseline values. Simvastatin, cantly greater than that observed with simvastatin alone combined therapy, and losartan significantly decreased the (PϽ0.001 by ANOVA). Simvastatin alone or combined therapy plasma MDA levels relative to baseline measurements by significantly lowered total cholesterol (both PϽ0.001), LDL 11Ϯ3% (PϽ0.001), 23Ϯ4% (PϽ0.001), and 5Ϯ3% cholesterol (both PϽ0.001), and apolipoprotein B levels (both (Pϭ0.040), respectively; however, combined therapy signif- PϽ0.001) compared with baseline. These reductions were sig- icantly reduced MDA levels more than simvastatin or losar- nificantly greater than those observed with losartan alone(PϽ0.001 by ANOVA). However, there were no significant tan alone (PϽ0.001 by ANOVA; Figure 2 and Table 2).
differences between simvastatin alone and combined therapy forthese parameters (Table 2).
Effects of Therapies on Markers of Inflammation
Simvastatin, combined therapy, and losartan significantly
Effects of Therapies on Vasomotor Function
decreased plasma MCP-1 levels relative to baseline measure- ments by 7Ϯ3% (Pϭ0.003), 15Ϯ3% (PϽ0.001), and 5Ϯ4% Simvastatin, combined therapy, and losartan significantly (Pϭ0.048), respectively, however, combined therapy signif- improved the percent flow-mediated dilator response to icantly decreased MCP-1 levels more than simvastatin or Effects of Simvastatin, Combined Therapy, and Losartan on Adiponectin Levels and Insulin Resistance in
Hypercholesterolemic, Hypertensive Patients
S indicates simvastatin; C, combined therapy; L, losartan; and ADP, adiponectin. Data are expressed as meanϮSEM or median (25th to 75th percentiles). There were no significant differences among each baseline value.
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December 14, 2004
Figure 1. Percent change in flow-mediated dilation from pre-
Figure 3. Percent change in MCP-1 levels from pretreatment
treatment values after treatment with simvastatin alone, com- values after treatment with simvastatin alone, combined therapy, bined therapy, and losartan alone (PϽ0.001 by ANOVA). Bars and losartan alone (Pϭ0.030 by ANOVA). Bars identify SEM.
to 5.27 (Pϭ0.002), respectively. These increases were signif- losartan alone (Pϭ0.030 by ANOVA; Figure 3 and Table 2).
icantly greater than those observed with simvastatin alone Simvastatin, combined therapy, and losartan significantly (PϽ0.001 by ANOVA; Figure 4 and Table 3). The 3 lowered plasma hsCRP levels relative to baseline measure- therapies did not have significantly different baseline insulin ments from 0.85 to 0.80 mg/L (Pϭ0.042), 0.85 to 0.65 mg/L and glucose levels. However, the magnitude of reduction of (Pϭ0.002), and 0.85 to 0.80 mg/L (Pϭ0.042), respectively; insulin with combined therapy or losartan alone was signifi- however, the magnitude of reduction among these 3 therapies cantly greater than with simvastatin alone (Pϭ0.041 by was not statistically significant (Pϭ0.146 by ANOVA).
ANOVA; Table 3). Combined therapy or losartan alone Effects of Therapies on Adiponectin and
significantly increased QUICKI relative to baseline measure- Insulin Resistance
ments by 7Ϯ3% (Pϭ0.032) and 7Ϯ3% (Pϭ0.042), respec- There were significant inverse correlations between body tively. These increases were significantly greater than those observed with simvastatin alone (Pϭ0.029 by ANOVA; (rϭϪ0.332, Pϭ0.023 before simvastatin; rϭϪ0.328, Figure 5 and Table 3). There were correlations between Pϭ0.024 before combined therapy; rϭϪ0.292, Pϭ0.046 percent changes in adiponectin levels and percent changes in before losartan). There were significant inverse correlations QUICKI (rϭ0.245, Pϭ0.097 after simvastatin; rϭ0.316, between baseline adiponectin levels and baseline triglyceride Pϭ0.030 after combined therapy; rϭ0.433, Pϭ0.002 after levels (rϭϪ0.351, Pϭ0.016 before simvastatin; rϭϪ0.325, losartan). There were inverse correlations between percent Pϭ0.026 before combined therapy; rϭϪ0.342, Pϭ0.019 changes in adiponectin levels and percent changes in insulin before losartan). There were significant correlations between (rϭϪ0.171, Pϭ0.251 after simvastatin; rϭϪ0.352, Pϭ0.015 baseline adiponectin levels and baseline HDL cholesterol after combined therapy; rϭϪ0.367, Pϭ0.011 after losartan).
levels (rϭ0.401, Pϭ0.005 before simvastatin; rϭ0.399, We investigated whether losartan-induced changes in the Pϭ0.006 before combined therapy; rϭ0.303, Pϭ0.039 be- percent flow-mediated dilator response to hyperemia, sero- fore losartan). Combined therapy and losartan alone signifi- logical markers of oxidant stress and inflammation, and cantly increased the plasma adiponectin levels relative to insulin resistance were mediated by a reduction in systolic or baseline measurements from 4.63 to 5.02 (PϽ0.001) and 4.19 Figure 4. Percent change in adiponectin levels from pretreat-
Figure 2. Percent change in MDA levels from pretreatment val-
ment values after treatment with simvastatin alone, combined ues after treatment with simvastatin alone, combined therapy, therapy, and losartan alone (PϽ0.001 by ANOVA). Bars iden- and losartan alone (PϽ0.001 by ANOVA). Bars identify SEM.
Simvastatin Combined With Losartan
3691
apy in the present study are consistent with experimental andclinical studies.21,28 Losartan therapy alone resulted in significant elevation of adiponectin levels, decreased insulin levels, and increasedinsulin sensitivity (assessed by QUICKI). The present studyis the first report demonstrating that losartan therapy canincrease adiponectin levels. Adiponectin is an adipose-derived factor that augments and mimics metabolic actions ofinsulin. Increasing adiponectin levels would be predicted toimprove both insulin sensitivity and endothelial function bymultiple mechanisms. Regulation of metabolic homeostasisand hemodynamic homeostasis may be coupled by vascularactions of insulin to stimulate production of NO.16 Thus, Figure 5. Percent change in QUICKI from pretreatment values
improvements in endothelial function may increase insulin after treatment with simvastatin alone, combined therapy, and sensitivity, whereas increased insulin sensitivity may improve losartan alone (Pϭ0.029 by ANOVA). Bars identify SEM.
endothelial function.12 Interestingly, in contrast to the effectsof combination therapy on flow-mediated dilation, MDA, diastolic blood pressure. There were no significant correla- CRP, and MCP-1, the beneficial effects of losartan therapy on tions between these changes and reduction of systolic blood adiponectin levels, insulin levels, and insulin sensitivity did pressure (Ϫ0.134ՅrՅ0.077) or between these changes and not increase further with combination therapy. This finding reduction of diastolic blood pressure (Ϫ0.295ՅrՅ0.172).
suggests that improving endothelial function per se (as After combined therapy, improvement in flow-mediated di- reflected by flow-mediated dilation) may not completely lation correlated with changes in MDA levels (rϭϪ0.422 and explain the effects of losartan or combined therapy to Pϭ0.003), MCP-1 levels (rϭ0.189 and Pϭ0.204), hsCRP improve insulin sensitivity. In other words, there may be (rϭϪ0.137 and Pϭ0.357), adiponectin levels additional mechanisms for losartan or combined therapy to (rϭ0.420 and Pϭ0.003), QUICKI (rϭ0.258 and Pϭ0.080), improve insulin sensitivity that are independent of endothelial and insulin levels (rϭϪ0.251 and Pϭ0.089).
function, eg, direct effects of losartan on glucose insulin–stimulated glucose uptake or promotion of adipogenic differ- Discussion
entiation of preadipocytes29 or induction of peroxisome pro- In our hypercholesterolemic, hypertensive cohort, simvastatin therapy alone significantly improved the lipid profile, differentiation in adipocytes.30 Effects of losartan or com- whereas losartan therapy alone significantly lowered blood bined therapy to increase adiponectin levels may in part pressure as expected. Comparable beneficial effects on both mediate improved insulin sensitivity, which is supported by lipids and blood pressure were observed with combination the significant correlation shown in the present study. On the therapy. We reasoned that distinct biological actions of other hand, combined therapy may reduce insulin resistance simvastatin and losartan therapies on lipoproteins and the by multiple mechanisms such as lipoprotein changes and angiotensin system may improve endothelium-dependent reduced oxidant stress that also contribute to NO bioavail- vascular function by different mechanisms. Indeed, although ability. The effects of losartan or combined therapy on monotherapy with simvastatin or losartan significantly im- flow-mediated dilation, oxidant stress and inflammation proved endothelial function and inflammatory markers (as- markers, and insulin resistance were independent of blood sessed by flow-mediated dilation, MDA levels, CRP levels, pressure changes and consistent with recent randomized and MCP-1 levels), combined therapy had additional substan- clinical trials.2,31 Likewise, several studies suggest a hypoth- tial and significant beneficial effects on these parameters over esis that the effects of AT1 receptor blockers to improve those seen with monotherapy for either drug, which may endothelial function are due to other factors in addition to a explain the observations of a recent clinical trial.21 The additional beneficial effects of combined simvastatin/ Metabolic syndrome is associated with atherosclerotic losartan therapy may be the result of several interacting disease. Patients with metabolic syndrome make up one of the mechanisms. For example, angiotensin II is very potent largest groups of individuals with both hyperlipidemia and endogenous vasoconstrictor, whereas LDL induces upregula- hypertension. Obesity is one of the most common causes of tion of the AT1 receptor.22 Indeed, hypercholesterolemic cardiovascular disease. In the present study, more than half of rabbits display enhanced vascular expression of AT1 recep- the subjects were overweight. We observed that plasma levels tors that mediate increased activity of angiotensin II.23 Fur- of adiponectin were significantly inversely correlated with thermore, the effect of statins to reverse the elevated blood body mass index. We also observed significant correlations pressure response to angiotensin II infusion is accompanied between baseline adiponectin levels and baseline HDL cho- by downregulated AT1 receptor density.24,25 Angiotensin II lesterol or triglyceride levels. Thus, our study may have promotes superoxide anion generation and endothelial dys- implications for the treatment of patients with metabolic function.8,26 CRP upregulates AT1 receptors in vascular smooth muscle cells, and these effects are attenuated by In summary, our study suggests that combination therapy losartan.27 The additive beneficial effects of combined ther- with simvastatin and losartan has beneficial additive effects 3692
Circulation
December 14, 2004
on endothelial function and inflammatory markers. This may coronary artery disease in men. Arterioscler Thromb Vasc Biol. 2003;23: be due to combined effects of the respective monotherapies to 15. Yu JG, Javorschi S, Hevener AL, et al. The effect of thiazolidinediones improve lipid profile, blood pressure, adiponectin levels, and on plasma adiponectin levels in normal, obese, and type 2 diabetic insulin sensitivity. The additive beneficial effects of com- subjects. Diabetes. 2002;51:2968 –2974.
bined therapy are predicted to reduce cardiovascular events in 16. Chen H, Montagnani M, Funahashi T, et al. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem.
hypercholesterolemic, hypertensive patients more than mono- 17. Ouchi N, Kihara S, Arita Y, et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger Acknowledgments
receptor expression in human monocyte-derived macrophages. Circu-lation. 2001;103:1057–1063.
This study was supported in part by grants from the Korea Society of 18. Koh KK, Jin DK, Yang SH, et al. Vascular effects of synthetic or natural Hypertension (KSH-2004). We express our gratitude to Han Gyu progestagen combined with conjugated equine estrogen in healthy post- Kim, MT, Sang Kyoon Kwon, MT, Jeong Bum Park, MT, Hyo Ju menopausal women. Circulation. 2001;103:1961–1966.
Park, BA, and Soo Jin Kim, RN, for their excellent technical 19. Katz A, Nambi SS, Mather K, et al. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity inhumans. J Clin Endocrinol Metab. 2000;85:2402–2410.
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